IL17RD

IL17RD
Identifiers
Aliases	IL17RD, HH18, IL-17RD, IL17RLM, SEF, interleukin 17 receptor D
External IDs	OMIM: 606807; MGI: 2159727; HomoloGene: 9717; GeneCards: IL17RD; OMA:IL17RD - orthologs
Gene location (Human)
Chr.	Chromosome 3 (human)
End	57,170,306 bp
Gene location (Mouse)
Chr.	Chromosome 14 (mouse)
End	26,829,243 bp
RNA expression pattern
	Top expressed in
	secondary oocyte; ; lactiferous duct; ; ganglionic eminence; ; corpus epididymis; ; tail of epididymis; ; parietal pleura; ; germinal epithelium; ; sperm; ; ventricular zone; ; tendon of biceps brachii;
	Top expressed in
	vestibular sensory epithelium; ; primitive streak; ; tail of embryo; ; Bowman's capsule; ; secondary oocyte; ; primary oocyte; ; zygote; ; mandibular prominence; ; vestibular membrane of cochlear duct; ; maxillary prominence;
	More reference expression data
	n/a
Gene ontology
Molecular function	interleukin-17 receptor activity;
Cellular component	cytoplasm; integral component of membrane; Golgi apparatus; membrane; Golgi membrane; plasma membrane; integral component of plasma membrane; nucleoplasm;
Biological process	MAPK cascade; cytokine-mediated signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	54756
	171463
	ENSG00000144730
	ENSMUSG00000040717
	Q8NFM7
	Q8JZL1
	NM_017563; NM_001318864
	NM_027265; NM_134437
	NP_001305793; NP_060033
	NP_602319
	Wikidata
View/Edit Human	View/Edit Mouse

Interleukin 17 receptor D (also known as Sef) is a protein that in humans is encoded by the IL17RD gene.^[5]

This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. Alternate splicing generates multiple transcript variants encoding distinct isoforms. IL-17RD has been described to limit fibroblast growth factor receptor (FGFR) signaling and to be a part of the IL-17 receptor signaling complex.

Identification

IL-17RD was initially discovered during a large-scale in situ hybridization screen for genes regulating zebrafish embryogenesis. It was identified as a part of a synexpression group (genes with similar spatio-temporal expression) with negative regulators of fibroblast growth factor (FGF) and termed Sef (similar expression to FGF genes). The name was later changed to IL-17RD due to its sequence similarity to other IL-17 receptors. It was further determined that IL-17RD co-immunoprecipitates with FGF receptor (FGFR) and inhibits FGF signaling at the level of signal transduction and not by interfering with the ligand or its binding to FGFR.^[6]^[7]

Structure

IL-17RD is a type I transmembrane protein containing extracellular Ig-like domain followed by a fibronectin type III domain, a short transmembrane domain of ~20 amino acids, and an intracellular SEFIR domain which was identified in IL-17 receptors and some soluble factors involved in IL-17 signaling.^[8] The SEFIR domain contains a region with sequence similarity to the TIR domain, which is characteristic of Toll-like receptors (TLRs), receptors of the interleukin 1 family, and adaptor proteins involved in the signaling pathways of these receptors. The regions within SEFIR that can be found in the TIR domain include box 1 and box 2.^[9]

IL-17RD in development

IL-17RD (Sef) was identified as part of a group of genes involved in FGF signaling in zebrafish and Xenopus laevis embryo. Injection of 1-cell stage embryo with sef mRNA lead to ventralization of the embryo, a similar effect observed after injection with XFD (a dominant negative of FGF receptor), suggesting its function as a negative regulator of FGF receptor signaling. Co-immunoprecipitation assay revealed that the intracellular part, but not the SEFIR domain, is critical for IL-17RD association with FGFR.^[6] One of the pathways activated by stimulation of FGFR is Ras/MAPK (the rest being PI3/AKT and PLCγ). Injection of embryos with high amounts of Ras, Raf or MEK causes cell cycle arrest, which can be rescued by co-injection of IL-17RD, further supporting the role of IL-17RD in negative regulation of FGFR signaling. Moreover, IL-17RD appears to regulate FGF signaling at the level of downstream signaling, not the receptor, since overexpression of FGF or FGFR does not cause cell cycle arrest.^[7] Taken together IL-17RD seems to negatively regulate FGFR signaling by limiting MAPK signaling via its intracellular domain.

IL-17RD in inflammation

IL-17 signaling

The IL-17 receptor family belongs to a group of structurally similar receptors with a distinctive SEFIR (Sef and IL-17R) domain.^[9] The founding member, IL-17RA, along with IL-17RC serve as a receptor complex for IL-17. IL-17 is a proinflammatory cytokine mainly produced by Th17 subset of T cells and plays an important role in extracellular pathogen elimination as well as several autoinflammatory diseases (such as psoriasis or rheumatoid arthritis).^[10] IL-17RD has been reported to associate and co-localize with IL-17RA, mediate IL-17 signaling, and interact with TRAF6 (an IL-17 downstream molecule). Moreover, deletion of IL-17RD intracellular domain has a dominant negative effect and suppresses IL-17 signaling. In contrast, deletion of extracellular domain had no effect on IL-17 signaling.^[11] However, full-body IL-17RD knockout mice do not present with any apparent phenotype.^[12] This might be accounted for by the presence of IL-17RC which to an extent substitutes IL-17RD. It is important to note, however, that IL-17RC or IL-17RD deletion fails to protect against imiquimod-induced psoriasis.^[13]

TLR signaling

Since the SEFIR domain contains a TIR domain, the possible role of IL-17RD in TLR signaling was investigated. One study discovered that IL-17RD interacts with TIR adaptor proteins (such as MyD88, Mal, and TRIF) following TLR stimulation. Additionally, this interaction was abolished in IL-17RD which lacks the SEFIR domain. The study concluded that IL-17RD targets TLR-induced pro-inflammatory pathways and inhibits signaling upstream of NF-κB and IRF3.^[14]

TNF signaling

One study reported that TNF induces IL-17RD expression, which then serves as a feedback loop inhibiting the activation of TNF-activated NF-κB.^[15] Another study focusing on renal cells describes IL-17RD to associate with TNFR2, but not TNFR1, to augment NF-κB activation.^[16] The contrasting results suggest different roles of IL-17RD in various tissues.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000144730 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000040717 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Entrez Gene: Interleukin 17 receptor D". Retrieved 2016-04-17.
^ ^a ^b Tsang M, Friesel R, Kudoh T, Dawid IB (February 2002). "Identification of Sef, a novel modulator of FGF signalling". Nature Cell Biology. 4 (2): 165–169. doi:10.1038/ncb749. PMID 11802164. S2CID 36494661.
^ ^a ^b Fürthauer M, Lin W, Ang SL, Thisse B, Thisse C (February 2002). "Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling". Nature Cell Biology. 4 (2): 170–174. doi:10.1038/ncb750. PMID 11802165. S2CID 32656219.
^ Pande S, Yang X, Friesel R (January 2021). "Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling". Cell Communication and Signaling. 19 (1): 6. doi:10.1186/s12964-020-00695-7. PMC 7805053. PMID 33436016.
^ ^a ^b Novatchkova M, Leibbrandt A, Werzowa J, Neubüser A, Eisenhaber F (May 2003). "The STIR-domain superfamily in signal transduction, development and immunity". Trends in Biochemical Sciences. 28 (5): 226–229. doi:10.1016/S0968-0004(03)00067-7. PMID 12765832.
^ Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (February 2006). "TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells". Immunity. 24 (2): 179–189. doi:10.1016/j.immuni.2006.01.001. PMID 16473830.
^ Rong Z, Wang A, Li Z, Ren Y, Cheng L, Li Y, et al. (February 2009). "IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling". Cell Research. 19 (2): 208–215. doi:10.1038/cr.2008.320. PMC 4603938. PMID 19079364.
^ Gaffen SL (August 2009). "Structure and signalling in the IL-17 receptor family". Nature Reviews. Immunology. 9 (8): 556–567. doi:10.1038/nri2586. PMC 2821718. PMID 19575028.
^ Su Y, Huang J, Zhao X, Lu H, Wang W, Yang XO, et al. (June 2019). "Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation". Science Immunology. 4 (36). doi:10.1126/sciimmunol.aau9657. PMID 31175175. S2CID 174805358.
^ Mellett M, Atzei P, Bergin R, Horgan A, Floss T, Wurst W, et al. (March 2015). "Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions". Nature Communications. 6 (1): 6669. Bibcode:2015NatCo...6.6669M. doi:10.1038/ncomms7669. PMID 25808990.
^ Fuchs Y, Brunwasser M, Haif S, Haddad J, Shneyer B, Goldshmidt-Tran O, et al. (September 2012). "Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic sequestration of NF-κB". Developmental Cell. 23 (3): 611–623. doi:10.1016/j.devcel.2012.07.013. PMID 22975329.
^ Yang S, Wang Y, Mei K, Zhang S, Sun X, Ren F, et al. (January 2015). "Tumor necrosis factor receptor 2 (TNFR2)·interleukin-17 receptor D (IL-17RD) heteromerization reveals a novel mechanism for NF-κB activation". The Journal of Biological Chemistry. 290 (2): 861–871. doi:10.1074/jbc.M114.586560. PMC 4294508. PMID 25378394.